tbuckley/cabot-search huggingface dataset:
Increased risk of osteoarthritis in patients with atopic disease
Authors: Matthew C Baker, Khushboo Sheth, Rong Lu, Di Lu, Ericka P von Kaeppler, Archana Bhat, David T Felson, William H Robinson
Journal: Annals of the Rheumatic Diseases (2023)

To determine the incidence of osteoarthrits (OA) in patients with atopic disease compared with matched non-exposed patients.We conducted a retrospective cohort study with propensity score matching using claims data from Optum's de-identified Clinformatics Data Mart (CDM) (January 2003 to June 2019) and electronic health record data from the Stanford Research Repository (STARR) (January 2010 to December 2020). We included adult patients without pre-existing OA or inflammatory arthritis who were exposed to atopic disease or who were non-exposed. The primary outcome was the development of incident OA.In Optum CDM, we identified 117 346 exposed patients with asthma or atopic dermatitis (mean age 52 years; 60% female) and 1 247 196 non-exposed patients (mean age 50 years; 48% female). After propensity score matching (n=1 09 899 per group), OA incidence was higher in patients with asthma or atopic dermatitis (26.9 per 1000 person-years) compared with non-exposed patients (19.1 per 1000 person-years), with an adjusted odds ratio (aOR) of 1.58 (95% CI 1.55 to 1.62) for developing OA. This effect was even more pronounced in patients with both asthma and atopic dermatitis compared with non-exposed patients (aOR=2.15; 95% CI 1.93 to 2.39) and in patients with asthma compared with patients with chronic obstructive pulmonary disease (aOR=1.83; 95% CI 1.73 to 1.95). We replicated our results in an independent dataset (STARR), which provided the added richness of body mass index data. The aOR of developing OA in patients with asthma or atopic dermatitis versus non-exposed patients in STARR was 1.42 (95% CI 1.36 to 1.48).This study demonstrates an increased incidence of OA in patients with atopic disease. Future interventional studies may consider targeting allergic pathways for the prevention or treatment of OA.
Apoptosis-induced nuclear expulsion in tumor cells drives S100a4-mediated metastatic outgrowth through the RAGE pathway
Authors: Woo-Yong Park, Justin M. Gray, Ronald J. Holewinski, Thorkell Andresson, Jae Young So, Carmelo Carmona-Rivera, M. Christine Hollander, Howard H. Yang, Maxwell Lee, Mariana J. Kaplan, Steven D. Cappell, Li Yang
Journal: Nature Cancer (2023)

Most tumor cells undergo apoptosis in circulation and at the metastatic organ sites due to host immune surveillance and a hostile microenvironment. It remains to be elucidated whether dying tumor cells have a direct effect on live tumor cells during the metastatic process and what the underlying mechanisms are. Here we report that apoptotic cancer cells enhance the metastatic outgrowth of surviving cells through Padi4-mediated nuclear expulsion. Tumor cell nuclear expulsion results in an extracellular DNA-protein complex that is enriched with receptor for advanced glycation endproducts (RAGE) ligands. The chromatin-bound RAGE ligand S100a4 activates RAGE receptors in neighboring surviving tumor cells, leading to Erk activation. In addition, we identified nuclear expulsion products in human patients with breast, bladder and lung cancer and a nuclear expulsion signature correlated with poor prognosis. Collectively, our study demonstrates how apoptotic cell death can enhance the metastatic outgrowth of neighboring live tumor cells.
Ageing as a software design flaw
Authors: João Pedro de Magalhães
Journal: Genome biology (2023)

Abstract Ageing is inherent to all human beings, yet why we age remains a hotly contested topic. Most mechanistic explanations of ageing posit that ageing is caused by the accumulation of one or more forms of molecular damage. Here, I propose that we age not because of inevitable damage to the hardware but rather because of intrinsic design flaws in the software, defined as the DNA code that orchestrates how a single cell develops into an adult organism. As the developmental software runs, its sequence of events is reflected in shifting cellular epigenetic states. Overall, I suggest that to understand ageing we need to decode our software and the flow of epigenetic information throughout the life course.
Integration of Feedforward and Feedback Information Streams in the Modular Architecture of Mouse Visual Cortex
Authors: Andreas Burkhalter, Rinaldo D. D'Souza, Weiqing Ji, Andrew M. Meier
Journal: Annual Review of Neuroscience (2023)

Radial cell columns are a hallmark feature of cortical architecture in many mammalian species. It has long been held, based on the lack of orientation columns, that such functional units are absent in rodent primary visual cortex (V1). These observations led to the view that rodent visual cortex has a fundamentally different network architecture than that of carnivores and primates. While columns may be lacking in rodent V1, we describe in this review that modular clusters of inputs to layer 1 and projection neurons in the layers below are prominent features of the mouse visual cortex. We propose that modules organize thalamocortical inputs, intracortical processing streams, and transthalamic communications that underlie distinct sensory and sensorimotor functions.
The Computational and Neural Bases of Context-Dependent Learning
Authors: James B. Heald, Daniel M. Wolpert, Máté Lengyel
Journal: Annual Review of Neuroscience (2023)

Flexible behavior requires the creation, updating, and expression of memories to depend on context. While the neural underpinnings of each of these processes have been intensively studied, recent advances in computational modeling revealed a key challenge in context-dependent learning that had been largely ignored previously: Under naturalistic conditions, context is typically uncertain, necessitating contextual inference. We review a theoretical approach to formalizing context-dependent learning in the face of contextual uncertainty and the core computations it requires. We show how this approach begins to organize a large body of disparate experimental observations, from multiple levels of brain organization (including circuits, systems, and behavior) and multiple brain regions (most prominently the prefrontal cortex, the hippocampus, and motor cortices), into a coherent framework. We argue that contextual inference may also be key to understanding continual learning in the brain. This theory-driven perspective places contextual inference as a core component of learning.
Global coverage of interventions to prevent and manage drug-related harms among people who inject drugs: a systematic review
Authors: Samantha Colledge-Frisby, Sophie Ottaviano, Paige Webb, Jason Grebely, Alice Wheeler, Evan B Cunningham, Behzad Hajarizadeh, Janni Leung, Amy Peacock, Peter Vickerman, Michael Farrell, Gregory J Dore, Matthew Hickman, Louisa Degenhardt
Journal: The Lancet Global Health (2023)

Harm reduction and treatment programmes are essential for reducing harms for people who inject drugs (PWID). We aimed to update estimates from a 2017 review of global coverage of needle and syringe exchange programmes (NSPs), opioid agonist treatment (OAT), and other harm reduction services that target PWID (eg, take-home naloxone [THN] programmes, supervised consumption facilities, and drug checking services).
Mortality and immune-related adverse events after immune checkpoint inhibitor initiation for cancer among patients with pre-existing rheumatoid arthritis: a retrospective, comparative, cohort study
Authors: Kaitlin R McCarter, Taylor Wolfgang, Senada Arabelovic, Xiaosong Wang, Kazuki Yoshida, Emily P Banasiak, Grace Qian, Emily N Kowalski, Kathleen M M Vanni, Nicole R LeBoeuf, Elizabeth I Buchbinder, Lydia Gedmintas, Lindsey A MacFarlane, Deepak A Rao, Nancy A Shadick, Ellen M Gravallese, Jeffrey A Sparks
Journal: The Lancet Rheumatology (2023)
Epidemiology of injecting drug use, prevalence of injecting-related harm, and exposure to behavioural and environmental risks among people who inject drugs: a systematic review
Authors: Louisa Degenhardt, Paige Webb, Samantha Colledge-Frisby, Jeremy Ireland, Alice Wheeler, Sophie Ottaviano, Alex Willing, Abe Kairouz, Evan B Cunningham, Behzad Hajarizadeh, Janni Leung, Lucy T Tran, Olivia Price, Amy Peacock, Peter Vickerman, Michael Farrell, Gregory J Dore, Matthew Hickman, Jason Grebely
Journal: The Lancet Global Health (2023)

People who inject drugs are exposed to various and changing risk environments and are at risk of multiple harms related to injecting drug use (IDU). We aimed to undertake a global systematic review of the prevalence of IDU, key IDU-related harms (including HIV, hepatitis C virus [HCV], and hepatitis B virus [HBV] infection and overdose), and key sociodemographic characteristics and risk exposures for people who inject drugs.
Incidence of HIV and hepatitis C virus among people who inject drugs, and associations with age and sex or gender: a global systematic review and meta-analysis
Authors: Adelina Artenie, Jack Stone, Hannah Fraser, Daniel Stewart, Chiedozie Arum, Aaron G Lim, Anna L McNaughton, Adam Trickey, Zoe Ward, Daniela Abramovitz, Michel Alary, Jacquie Astemborski, Julie Bruneau, Steven J Clipman, Carla S Coffin, Sara Croxford, Kora DeBeck, Eva Emanuel, Kanna Hayashi, Joumana G Hermez, Daniel Low-Beer, Niklas Luhmann, Gisela Macphail, Lisa Maher, Norah E Palmateer, Eshan U Patel, Rachel Sacks-Davis, Wijnand Van Den Boom, Daniela K van Santen, Josephine G Walker, Matthew Hickman, Peter Vickerman
Journal: The Lancet. Gastroenterology & hepatology (2023)

Measuring the incidence of HIV and hepatitis C virus (HCV) infection among people who inject drugs (PWID) is key to track progress towards elimination. We aimed to summarise global data on HIV and primary HCV incidence among PWID and associations with age and sex or gender.
Dostarlimab for Primary Advanced or Recurrent Endometrial Cancer
Authors: Mansoor R. Mirza, Dana M. Chase, Brian M. Slomovitz, René dePont Christensen, Zoltán Novák, Destin Black, Lucy Gilbert, Sudarshan Sharma, Giorgio Valabrega, Lisa M. Landrum, Lars C. Hanker, Ashley Stuckey, Ingrid Boere, Michael A. Gold, Annika Auranen, Bhavana Pothuri, David Cibula, Carolyn McCourt, Francesco Raspagliesi, Mark S. Shahin, Sarah E. Gill, Bradley J. Monk, Joseph Buscema, Thomas J. Herzog, Larry J. Copeland, Min Tian, Zangdong He, Shadi Stevens, Eleftherios Zografos, Robert L. Coleman, Matthew A. Powell
Journal: New England Journal of Medicine (2023)

Dostarlimab is an immune-checkpoint inhibitor that targets the programmed cell death 1 receptor. The combination of chemotherapy and immunotherapy may have synergistic effects in the treatment of endometrial cancer.We conducted a phase 3, global, double-blind, randomized, placebo-controlled trial. Eligible patients with primary advanced stage III or IV or first recurrent endometrial cancer were randomly assigned in a 1:1 ratio to receive either dostarlimab (500 mg) or placebo, plus carboplatin (area under the concentration-time curve, 5 mg per milliliter per minute) and paclitaxel (175 mg per square meter of body-surface area), every 3 weeks (six cycles), followed by dostarlimab (1000 mg) or placebo every 6 weeks for up to 3 years. The primary end points were progression-free survival as assessed by the investigator according to Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1, and overall survival. Safety was also assessed.Of the 494 patients who underwent randomization, 118 (23.9%) had mismatch repair-deficient (dMMR), microsatellite instability-high (MSI-H) tumors. In the dMMR-MSI-H population, estimated progression-free survival at 24 months was 61.4% (95% confidence interval [CI], 46.3 to 73.4) in the dostarlimab group and 15.7% (95% CI, 7.2 to 27.0) in the placebo group (hazard ratio for progression or death, 0.28; 95% CI, 0.16 to 0.50; P<0.001). In the overall population, progression-free survival at 24 months was 36.1% (95% CI, 29.3 to 42.9) in the dostarlimab group and 18.1% (95% CI, 13.0 to 23.9) in the placebo group (hazard ratio, 0.64; 95% CI, 0.51 to 0.80; P<0.001). Overall survival at 24 months was 71.3% (95% CI, 64.5 to 77.1) with dostarlimab and 56.0% (95% CI, 48.9 to 62.5) with placebo (hazard ratio for death, 0.64; 95% CI, 0.46 to 0.87). The most common adverse events that occurred or worsened during treatment were nausea (53.9% of the patients in the dostarlimab group and 45.9% of those in the placebo group), alopecia (53.5% and 50.0%), and fatigue (51.9% and 54.5%). Severe and serious adverse events were more frequent in the dostarlimab group than in the placebo group.Dostarlimab plus carboplatin-paclitaxel significantly increased progression-free survival among patients with primary advanced or recurrent endometrial cancer, with a substantial benefit in the dMMR-MSI-H population. (Funded by GSK; RUBY ClinicalTrials.gov number, NCT03981796.).
Cases in Precision Medicine: Is There an Obligation to Return Reinterpreted Genetic Results to Former Patients?
Authors: Paul S. Appelbaum, Wylie Burke, Erik Parens, Jessica Roberts, Sara M. Berger, Wendy K. Chung
Journal: Annals of Internal Medicine (2023)

Interpretation of many genetic test results can change over time as new data accumulate. Hence, physicians who order genetic tests may subsequently receive revised reports with important implications for patients' medical treatment—even for patients who are no longer in their care. Several of the ethical principles underlying medical practice suggest an obligation to reach out to former patients with this information. Discharging that obligation can be accomplished, at a minimum, by attempting to contact the former patient with their last known contact information.
Pembrolizumab plus Chemotherapy in Advanced Endometrial Cancer
Authors: Ramez N. Eskander, Michael W. Sill, Lindsey Beffa, Richard G. Moore, Joanie M. Hope, Fernanda B. Musa, Robert Mannel, Mark S. Shahin, Guilherme H. Cantuaria, Eugenia Girda, Cara Mathews, Juraj Kavecansky, Charles A. Leath, Lilian T. Gien, Emily M. Hinchcliff, Shashikant B. Lele, Lisa M. Landrum, Floor Backes, Roisin E. O’Cearbhaill, Tareq Al Baghdadi, Emily K. Hill, Premal H. Thaker, Veena S. John, Stephen Welch, Amanda N. Fader, Matthew A. Powell, Carol Aghajanian
Journal: New England Journal of Medicine (2023)

Standard first-line chemotherapy for endometrial cancer is paclitaxel plus carboplatin. The benefit of adding pembrolizumab to chemotherapy remains unclear. Download a PDF of the Research Summary. In this double-blind, placebo-controlled, randomized, phase 3 trial, we assigned 816 patients with measurable disease (stage III or IVA) or stage IVB or recurrent endometrial cancer in a 1:1 ratio to receive pembrolizumab or placebo along with combination therapy with paclitaxel plus carboplatin. The administration of pembrolizumab or placebo was planned in 6 cycles every 3 weeks, followed by up to 14 maintenance cycles every 6 weeks. The patients were stratified into two cohorts according to whether they had mismatch repair–deficient (dMMR) or mismatch repair–proficient (pMMR) disease. Previous adjuvant chemotherapy was permitted if the treatment-free interval was at least 12 months. The primary outcome was progression-free survival in the two cohorts. Interim analyses were scheduled to be triggered after the occurrence of at least 84 events of death or progression in the dMMR cohort and at least 196 events in the pMMR cohort. In the 12-month analysis, Kaplan–Meier estimates of progression-free survival in the dMMR cohort were 74% in the pembrolizumab group and 38% in the placebo group (hazard ratio for progression or death, 0.30; 95% confidence interval [CI], 0.19 to 0.48; P<0.001), a 70% difference in relative risk. In the pMMR cohort, median progression-free survival was 13.1 months with pembrolizumab and 8.7 months with placebo (hazard ratio, 0.54; 95% CI, 0.41 to 0.71; P<0.001). Adverse events were as expected for pembrolizumab and combination chemotherapy. In patients with advanced or recurrent endometrial cancer, the addition of pembrolizumab to standard chemotherapy resulted in significantly longer progression-free survival than with chemotherapy alone. (Funded by the National Cancer Institute and others; NRG-GY018 ClinicalTrials.gov number, NCT03914612.) QUICK TAKE VIDEO SUMMARYPembrolizumab in Advanced Endometrial Cancer 02:16
Effect of Medicare Advantage on Hospital Readmission and Mortality Rankings
Authors: Andrew S. Oseran, Rishi K. Wadhera, E. John Orav, Jose F. Figueroa
Journal: Annals of Internal Medicine (2023)

Medicare links hospital performance on readmissions and mortality to payment solely on the basis of outcomes among fee-for-service (FFS) beneficiaries. Whether including Medicare Advantage (MA) beneficiaries, who account for nearly half of all Medicare beneficiaries, in the evaluation of hospital performance affects rankings is unknown.To determine if the inclusion of MA beneficiaries in readmission and mortality measures reclassifies hospital performance rankings compared with current measures.Cross-sectional.Population-based.Hospitals participating in the Hospital Readmissions Reduction Program or Hospital Value-Based Purchasing Program.Using the 100% Medicare files for FFS and MA claims, the authors calculated 30-day risk-adjusted readmissions and mortality for acute myocardial infarction, heart failure, chronic obstructive pulmonary disease, and pneumonia on the basis of only FFS beneficiaries and then both FFS and MA beneficiaries. Hospitals were divided into quintiles of performance based on FFS beneficiaries only, and the proportion of hospitals that were reclassified to a different performance group with the inclusion of MA beneficiaries was calculated.Of the hospitals in the top-performing quintile for readmissions and mortality based on FFS beneficiaries, between 21.6% and 30.2% were reclassified to a lower-performing quintile with the inclusion of MA beneficiaries. Similar proportions of hospitals were reclassified from the bottom performance quintile to a higher one across all measures and conditions. Hospitals with a higher proportion of MA beneficiaries were more likely to improve in performance rankings.Hospital performance measurement and risk adjustment differed slightly from those used by Medicare.Approximately 1 in 4 top-performing hospitals is reclassified to a lower performance group when MA beneficiaries are included in the evaluation of hospital readmissions and mortality. These findings suggest that Medicare's current value-based programs provide an incomplete picture of hospital performance.Laura and John Arnold Foundation.
Differential Efficacy From the Addition of Bortezomib to R-CHOP in Diffuse Large B-Cell Lymphoma According to the Molecular Subgroup in the REMoDL-B Study With a 5-Year Follow-Up
Authors: Andrew J. Davies, Sharon Barrans, Louise Stanton, Josh Caddy, Sam Wilding, Geoff Saunders, Christoph Mamot, Urban Novak, Andrew McMillan, Paul Fields, Graham P. Collins, Richard Stephens, Francesco Cucco, Chulin Sha, Moniek van Hoppe, Reuben Tooze, John R. Davies, Gareth Griffiths, Anna Schuh, Catherine Burton, David R. Westhead, Ming-Qing Du, Peter W.M. Johnson
Journal: Journal of Clinical Oncology (2023)

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported. The REMoDL-B phase III adaptive trial compared rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone (R-CHOP) versus R-CHOP + bortezomib (RB-CHOP) in patients with diffuse large B-cell lymphoma (DLBCL), stratified by molecular subtype. Primary analysis at a median follow-up of 30 months found no effect of bortezomib on progression-free survival (PFS) or overall survival (OS). Retrospective analysis using a gene expression–based classifier identified a molecular high-grade (MHG) group with worse outcomes. We present an updated analysis for patients successfully classified by the gene expression profile (GEP). Eligible patients were age older than 18 years with untreated DLBCL, fit enough for full-dose chemotherapy, and with adequate biopsies for GEP. Of 1,077 patients registered, 801 were identified with Activated B-Cell (ABC), Germinal Center B-cell, or MHG lymphoma. At a median follow-up of 64 months, there was no overall benefit of bortezomib on PFS or OS (5-year PFS hazard ratio [HR], 0.81; P = .085; OS HR, 0.86; P = .32). However, improved PFS and OS were seen in ABC lymphomas after RB-CHOP: 5-year OS 67% with R-CHOP versus 80% with RB-CHOP (HR, 0.58; 95% CI, 0.35 to 0.95; P = .032). Five-year PFS was higher in MHG lymphomas: 29% versus 55% (HR, 0.46; 95% CI, 0.26 to 0.84). Patients with ABC and MHG DLBCL may benefit from the addition of bortezomib to R-CHOP in initial therapy.
Subclinical Coronary Atherosclerosis and Risk for Myocardial Infarction in a Danish Cohort
Authors: Andreas Fuchs, Jørgen Tobias Kühl, Per Ejlstrup Sigvardsen, Shoaib Afzal, Andreas Dehlbæk Knudsen, Mathias Bech Møller, Martina Chantal de Knegt, Mathias Holm Sørgaard, Børge Grønne Nordestgaard, Lars Valeur Køber, Klaus Fuglsang Kofoed
Journal: Annals of Internal Medicine (2023)

Coronary atherosclerosis may develop at an early age and remain latent for many years.To define characteristics of subclinical coronary atherosclerosis associated with the development of myocardial infarction.Prospective observational cohort study.Copenhagen General Population Study, Denmark.9533 asymptomatic persons aged 40 years or older without known ischemic heart disease.Subclinical coronary atherosclerosis was assessed with coronary computed tomography angiography conducted blinded to treatment and outcomes. Coronary atherosclerosis was characterized according to luminal obstruction (nonobstructive or obstructive [≥50% luminal stenosis]) and extent (nonextensive or extensive [one third or more of the coronary tree]). The primary outcome was myocardial infarction, and the secondary outcome was a composite of death or myocardial infarction.A total of 5114 (54%) persons had no subclinical coronary atherosclerosis, 3483 (36%) had nonobstructive disease, and 936 (10%) had obstructive disease. Within a median follow-up of 3.5 years (range, 0.1 to 8.9 years), 193 persons died and 71 had myocardial infarction. The risk for myocardial infarction was increased in persons with obstructive (adjusted relative risk, 9.19 [95% CI, 4.49 to 18.11]) and extensive (7.65 [CI, 3.53 to 16.57]) disease. The highest risk for myocardial infarction was noted in persons with obstructive-extensive subclinical coronary atherosclerosis (adjusted relative risk, 12.48 [CI, 5.50 to 28.12]) or obstructive-nonextensive (adjusted relative risk, 8.28 [CI, 3.75 to 18.32]). The risk for the composite end point of death or myocardial infarction was increased in persons with extensive disease, regardless of degree of obstruction-for example, nonobstructive-extensive (adjusted relative risk, 2.70 [CI, 1.72 to 4.25]) and obstructive-extensive (adjusted relative risk, 3.15 [CI, 2.05 to 4.83]).Mostly White persons were studied.In asymptomatic persons, subclinical, obstructive coronary atherosclerosis is associated with a more than 8-fold elevated risk for myocardial infarction.AP Møller og Hustru Chastine Mc-Kinney Møllers Fond.